Feb 17, 2012 - Ozonoff S, Iosi A, Baguio F, Cook IC, Hill MM, Hutman T, Rog- ers SJ, Rozga A, .... Computing and Imaging Institute, University of Utah, Salt Lake City; ... Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM,.
A r t ic le
D iffe re n c e s in W h ite M a tte r F ib e r Tra c t D e v e lo p m e n t P re se n t Fro m 6 to 2 4 M o n th s in In fa n ts W ith A u tism Jason J. Wolff, Ph.D.
Robert C. McKinstry, M.D., Ph.D.
Hongbin Gu, Ph.D.
Sarah J. Paterson, Ph.D.
Guido Gerig, Ph.D.
Robert T. Schultz, Ph.D.
Jed T. Elison, Ph.D.
Lonnie Zwaigenbaum, M.D.
Martin Styner, Ph.D.
Joseph Piven, M.D.
Sylvain Gouttard, M.S.
For the IBIS Network
Kelly N. Botteron, M.D.
O b je c tiv e : Evidence from prospective studies of high-risk infants suggests that early sym ptom s of autism usually em erge late in the first or early in the second year of life after a period of relatively typical developm ent. The authors prospectively exam ined w hite m atter fiber tract organization from 6 to 24 m onths in high-risk infants w ho developed autism spectrum disorders (ASD s) by 24 m onths.
Stephen R. Dager, M.D. Geraldine Dawson, Ph.D. Annette M. Estes, Ph.D. Alan C. Evans, Ph.D. Heather C. Hazlett, Ph.D. Penelope Kostopoulos, Ph.D.
M e th o d : The participants w ere 92 highrisk infant siblings from an ongoing im aging study of autism . All participants had diffusion tensor im aging at 6 m onths and behavioral assessm ents at 24 m onths; a
m ajority contributed additional im aging data at 12 and/or 24 m onths. At 24 m onths, 28 infants m et criteria for ASD s and 64 infants did not. M icrostructural properties of w hite m atter fiber tracts reported to be associated w ith ASD s or related behaviors w ere characterized by fractional anisotropy and radial and axial diffusivity. R e s u lts : The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly betw een the infants w ho developed ASD s and those w ho did not. D evelopm ent for m ost fiber tracts in the infants w ith ASD s w as characterized by higher fractional anisotropy values at 6 m onths follow ed by slow er change over tim e relative to infants w ithout ASD s. Thus, by 24 m onths of age, those w ith ASD s had low er values. C o n c lu s io n s : These results suggest that aberrant developm ent of w hite m atter pathw ays m ay precede the m anifestation of autistic sym ptom s in the first year of life. Longitudinal data are critical to characterizing the dynam ic age-related brain and behavior changes underlying this neurodevelopm ental disorder. (A m J P sy c h ia try W o lff e t a l.; A iA :1 –1 2 )
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utism spectrum disorders (ASDs) are complex disorders of neurodevelopment defined by impaired social communication and restricted, repetitive behaviors. ASDs represent a significant public health concern, affecting upward of one in 110 children, with a recurrence rate among at-risk families of nearly one in five (1, 2). Findings from prospective studies of infant siblings of children with ASDs, who are at higher than average risk for the disorder, indicate that a number of the defining behavioral features of ASDs first emerge around 12 months of age after a period of relatively typical postnatal development (3–5). Although several studies have documented the early behavioral course of infants later diagnosed with ASDs, we know of no published neuroimaging data on such infants before toddlerhood. Existing studies have provided evidence from magnetic resonance imaging (MRI) of significantly larger than normal brain volume in 2- and 3-year olds with ASDs (6–10). These findings are consistent with A JP in A dva n ce
reports of higher than normal brain weight in postmortem brains of individuals with autism (11), as well as numerous reports associating ASDs with large head circumference (12). Two large retrospective studies suggest that the onset of this larger head circumference likely occurs in the latter part of the first year of life (7, 13). Taken together, findings from the behavioral studies and the studies of brain and head size growth in high-risk infant siblings suggest that the latter half of the first year of life is a pivotal time for both brain changes and symptom onset in infants later diagnosed with an ASD. The concurrent timing of these phenomena suggests that brain changes during this period may have an important role in the pathogenesis of autistic behavior. Autism is increasingly considered a disorder characterized in part by aberrant neural circuitry (14, 15). Functional neuroimaging studies have revealed patterns of disrupted connectivity in adults (16) and children (17, 18) a jp.p sych ia tryo n lin e.o rg
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with ASDs. A growing body of work has employed diffusion tensor imaging to gauge the microstructural properties of white matter circuitry (19, 20). Studies of ASDs using diffusion tensor imaging have identified evidence of widespread abnormalities in white matter fiber tract integrity (21–25), with cross-sectional studies indicating less age-related change in children and adolescents with ASDs than in typical comparison subjects (26, 27). While the preponderance of existing work suggests altered white matter development in ASDs, the extent, direction, and developmental course of these differences remain unclear (28). Fundamentally a disorder of development, autism emerges early in life and is generally associated with lifelong disability (29). When development itself is intrinsic to the phenomenon in question, it is prudent to seek answers from developmental trajectories (30–32). This is particularly so in the earliest periods of infancy, when dramatic changes in behavior are paralleled by dramatic changes in the brain. White matter pathways, for instance, rapidly develop during the first years of life, after which change is attenuated (33). However, to our knowledge, there have been no longitudinal studies of neural circuitry in ASDs, and but a few concerning volumetric brain development (8, 34, 35). Although numerous cross-sectional studies of children with ASDs posit key neurological changes relevant to the disorder, few have employed a true developmental perspective. As Karmiloff-Smith (36) aptly observed, crosssectional neuroimaging studies of children are not tantamount to neuroimaging studies of development. We present here a prospective, longitudinal study of white matter fiber tract development at 6, 12, and 24 months of age in infants who were at high risk for ASDs by virtue of having an older sibling with autism. In this study, we compared the subset of high-risk infants who showed evidence of ASDs by 24 months of age to those who did not. Given that both groups had a higher familial liability for ASDs than the general population, this design allowed for inferences not afforded to comparisons of high-risk children with ASDs and children at low familial risk. The focus of this study was on the development of white matter pathways selected on the basis of reported associations with ASDs or their core behavioral features (21–28).
M e th o d P a rtic ip a n ts This study included data from an Autism Center of Excellence funded by the National Institutes of Health. The Infant Brain Imaging Study (IBIS), the parent network, is an ongoing study of infants at risk for autism. Four clinical data collection sites are associated with the study: University of North Carolina, Chapel Hill; University of Washington, Seattle; Children’s Hospital of Philadelphia; and Washington University, St. Louis. Data were coordinated through the Montreal Neurological Institute (MNI) at McGill University, and data processing was performed at the University of North Carolina and the Scientific Computing and Imaging Institute at the University of Utah. The parent study en-
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rolled and assessed 6-month-old high-risk infants who were seen for follow-up assessments at 12 and 24 months of age. Written informed consent was obtained from parents or legal guardians before enrollment, and the study procedures were approved by institutional review boards at each site. The exclusionary criteria were 1) a significant medical condition known to affect brain development, 2) sensory impairment, 3) low birth weight (
